Open AccessHigh‐frequency haplotypes in the X chromosome locus TLR8 are associated with both CD and UC in females
Author(s) -
Saruta Masayuki,
Targan Stephan R.,
Mei Ling,
Ippoliti Andrew F.,
Taylor Kent D.,
Rotter Jerome I.
Publication year - 2009
Publication title -
inflammatory bowel diseases
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.932
H-Index - 146
eISSN - 1536-4844
pISSN - 1078-0998
DOI - 10.1002/ibd.20754
Subject(s) - haplotype , single nucleotide polymorphism , odds ratio , immunology , inflammatory bowel disease , nod2 , case control study , biology , medicine , genetics , disease , immune system , genotype , gene , innate immune system
Background: TNF‐α and IL‐1 have been associated with mucosal inflammation in both Crohn's disease (CD) and ulcerative colitis (UC). Innate immune defects have been associated with CD, specifically CARD15 / NOD2 . Recently, Toll‐like receptor 8 (TLR8) signaling has been shown to enhance generation of both cytokines. Interestingly, TLR8 is located on the X chromosome and inflammatory bowel disease (IBD) has been associated with abnormalities of the X chromosome. The aim was to test whether TLR8 haplotypes are associated with IBD. Methods: Subjects (735 CD, 343 UC, 245 controls) were genotyped. Single nucleotide polymorphisms (SNPs) were chosen to tag common Caucasian haplotypes. Results: Both “risk (H4)” and “protective (H1)” TLR8 haplotypes were observed associated with CD in females. Eighteen percent of CD females had H4 compared with 9% of controls ( P = 0.02). Fifty‐nine percent of CD females had H1 compared with 72% of controls ( P = 0.01). H1 was also negatively associated with UC in females (59% of UC, 72% of controls P = 0.03). Diplotype analysis of CD, UC, and all IBD in females revealed that 2 protective haplotypes (H1/H1) had a markedly diminished odds ratio, 0.4–0.5. The presence of a risk haplotype (H4 / not H1) had a significantly increased odds ratio, 2.0–2.2. Thus, the risk for IBD was 4–5 times higher in females with 1 risk haplotype than with the protective/protective diplotype. Conclusions: TLR8 is an X‐linked IBD susceptibility gene with both common predisposing and protecting haplotypes. These associations further emphasize the importance of genetic variation in innate immunity as determinants, not only of CD, but of UC as well. (Inflamm Bowel Dis 2008)